Chlorpheniramine maleate is classified under antihistaminic class of drugs. It is a propylamine derived function ( alkyl aminoalkanes ) , with a molecular weight of 390.9 Da. CPM is a H1 – receptor adversary and are used in the intervention of allergic reaction. CPM prevents but non change by reversal the responses which are produced by histamine. CPM antagonizes the pharmacological effects of histamine like urtications and pruritus ( Repka M.A, et.al. , 1999 and Michael A.R, et.al. , 2001 ) . They provide effectual impermanent alleviation of sneeze, watery and antsy eyes and running nose due to hay febrility and other upper respiratory piece of land allergic reactions. CPM are available in different dose signifiers like capsules, suspension sirup and tablets.
In instance of capsules ( drawn-out release, unwritten ) they are present in the signifier of maleate ( 8mg, 12 milligram ) , in instance of suspension ( unwritten ) in the signifier of tannate. In instance of sirup as maleate and in instance of tablet besides it is present in the signifier of maleate ( 4 milligram ) .
Certain trade names of CPM which are available in the above said dose signifiers attention: CPM -12 ( unwritten extended release capsules ) , Pedia TanTM ( unwritten suspension ) , Allerchlor® ( sirup and tablet ) , chlor – Trimeton® Allergy ( unwritten extended release tablets ) .
Some of the international trade names of CPM are Ahiston, Alerfin, Alergitrat, Antamin Barominic, Bregamin, Cadistin, Chloramine, chlorleate, Detista, Derimeton, Histatapp, Istamex, Niramine, Orphen, Pirafene, Piriton, Trimeton, tromine ( CPM: Drug information provided by Lexi comp ) .
CPM is a cationic amphiphilic amine drug ( CAD ) . It has got a hydrophobic ring construction and a hydrophilic side concatenation with a charged cationic amino group. This physico chemical belongings of CPM is similar to other CAD ‘s and hence was choosen as a exemplary drug for the present survey ( Andronis V, et.al. , 1995 ) .
Drug delivered through the transdermic path gets absorbed straight to the blood watercourse and hence reduces the hazard of GI side effects. And besides transdermic preparation bypasses the first base on balls metamorphosis in the liver and at that place by gives better effectivity when compared to other paths.
To cut down the frequence of dosage, to give better extended release action and to minimise the side consequence which was seen with the other dose signifiers of CPM ; CPM was formulated in the signifier of transdermic drug bringing system.
TRANS DERMAL DRUG DELIVERY SYSTEM
A transdermic spot is a medicated adhesive spot placed on the tegument to present a clip released dosage of medicine through the tegument for handling topical or systemic unwellness.
From early 1990, these dose signifier are available in the market. These systems provides important clinical benefits over other systems, such as tablets and injection ( Ranade V.V, 1991, Modamio P, 2000 and Ke GM, et.al. , 2005 ) .
TDDS delivers medicine to systemic circulation in a more suited and successful manner when compared to conventional dose signifier. The tegument has a greater possible as a way of drug disposal, which is confirmed by the acceptableness of marketed curative system ( Bhalla HL, et.al. , 1994 ) .
Administration of systemic drugs utilizing transdermic spot improved patient conformity. Transdermal path of disposal prevents the transition through gastero- enteric piece of land and at that place by maintain changeless plasma degrees for longer period of clip ( Nicoli S, et.al. , 2005 ) .
In instance of transdermic path of disposal, side effects gets decreased due to the reduced extremum plasma concentration of the drugs. It besides avoids the presystemic and systemic first base on balls metamorphosis and thereby eliminates the demand of endovenous entree ( Guy RH, 1996, Tiwary AK, et.al. , 2007 and Code G, et.al. , 1987 ) .
Transdermal path is a possible signifier of bringing of lipotropic drugs ( Schaefer H, et.al. , 1982 ) . This path controls country of application, measure applied, let go of dynamicss and the protraction of the application clip ( Tymes NW et.al. , 1990 ) .
ADVANTAGES OF T.D.D.S
1. Avoids first base on balls consequence ( drug inactivation by digestive and liver enzymes )
2. It is a replacement for unwritten path
3. Avoids vagaries associated with gastro enteric soaking up due to pH, enzymatic activity and nutrient interactions.
4. It avoids the hazards and incommodiousnesss of IV therapy.
5. Provides predictable drawn-out continuance of activity.
6. Extends the activity of drugs with short half lives.
7. Multiday therapy with individual application.
8. Provides capacity to end drug effects quickly.
9. Rapid designation of medicine in exigency.
Eg: Unconscious coma patients.
10. Minimize inter and intra patient fluctuation.
11. Reduces daily dosing, therefore bettering patient conformity.
1. Limited clip that the spot can stay affixed.
2. Variable intra and inter individual transdermal soaking up efficiency.
3. Skin roseolas and sensitisation.
4. Bacterial and enzymatic drug metamorphosis under the spot.
5. Complex engineering / high cost.
Section OF DRUG CANDIDATES FOR TRANS DERMAL DELIVERY
The choice of drug for the transdermic bringing is a hard one and one must take careful considerations for the choice of suited drug molecule. Some of the desirable belongingss that the drug should possess is given below ( Guy RH, et.al. , 1989 )
Physio-chemical belongingss of drug
1. The drug must hold a molecular weight less than 750 Da.
2. The drug should possess balanced lipotropic hydrophilic features and besides have sensible solubility in both liquid and aqueous stages.
3. The log P value should be in the scope of 0.5-3.
4. The runing point should be less than 200 degree celcious.
5. Saturated aqueous solution of the drug should hold pH value between 5 and 9.
BIOLOGICAL PROPERTIES OF DRUG
1. The biological half life ( t? ) should be less than 5-6 hours.
2. The drug should be powerful with day-to-day systemic dosage of less than 20 milligram.
3. The drug should non excite an immune reaction in the tegument.
4. The drug must non bring on a cutaneal thorn or allergic response.
SKIN STRUCTURE AND BARRIER PROPERTIES
Skin is most widely accessible organ in the organic structure. Protection, temperature ordinance, control of H2O end product and esthesis are its main map. The surface country covered by the tegument of an mean organic structure is 2 Sq. Mts. In instance of grownups it varies in thickness from 1.5 to 4 millimeters and weighing about 2 kilograms. Skin receives about one tierce of the blood go arounding through the organic structure ( Jacobs W, et.al. , 1970 ) . The outer most cellular bed of the tegument is epidermis. Following to that is the cellular connective tissue matrix corium. The construction of the tegument is given below in Fig. 1.
Fig. 1 Structure of tegument
Between these two beds there is a sub- microscopic construction called basal lamina which is derived from both the cuticle and corium and it acts as an anchoring construction.
The cuticle consists of two parts: the life cells of the malphygian bed ( stratum horny layer ) . Epidermis is improved of H cell types and they are keratinocytes, which constitutes around 80 % of the cuticle, melanocytes which are the beginning of the melanin pigment ; langerhans cells, they are outermost arm of the immunologic system and serves in host defence ; Merkel cells – they are thought to work as mechanoreceptors for esthesiss. Keratinocytes organize into strata with in the cuticle from inside to outside, stratum germinatum, stratum spinosum and stratum horny layer.
Stratum horny layer consists of 10 to 15 cell beds and is 10 millimeter midst in dry status. The membrane consists of dead anucleate, keratinized cells which are embedded in the lipid matrix. They are indispensable for commanding the transdermal soaking up of most of the drugs and chemicals. The horny bed has got an barrier nature due to its constitutents, 75-80 % proteins, 5-15 % lipoids and 5-10 % unidentified stuff on a dry weight footing ( Goldsmith LA, 1983 ) . The protein fraction consists of ceratin fibrils cross linked by inter molecular disulfide Bridgess
( Sun TT, et.al. , 1976 ) . Lipid sphere consists of organized distribution of intercellular gill obtained from intra cellular granules which are secreted during the epithelial distinction procedure ( Wertz PW, et.al. , 1982 ) .
Dermis has got an thickness of 3 to 5 millimeters and are composed of a matrix of connective tissue which contains packages of collagen filaments which interlace with elastic tissue and sparse reticular fibres ( Goldsmith LA, 1983 ) .
Fundamentalss OF SKIN PERMEATION
The sequence in which transdermic pervasion of drug occurs is given in Fig. 2.
Fig. 2 Diagrammatic representation of the Transdermal drug pervasion and drug consumption by the tegument.
The rate of drug pervasion, dQ/dt across the tegument can be given by the undermentioned relationship ( Chein YW, 1987 ) .
dQ/dt = Ps ( Cd-Cr )
where Cadmium and Cr, severally are the concentration of tegument penetrant in donor compartment ( eg. the drug concentration on surface of stratum horny layer ) and in receptor compartment ( eg.body ) . Ps the permeableness coefficient of tegument tissues to the penetrant as defined by
Ps = Ks Dss / Hs
where Ks is the divider coefficient of interfacial breakdown of penetrant molecule from solution medium or a TDDS on a stratum horny layer ; Dss is evident diffusivity for steady province diffusion of the penetrant through a thickness of skin tissues ; and hs the thickness of skin tissues.
From Eq.1 to accomplish a changeless rate of drug pervasion, consistence of the drug concentration on the surface of stratum horny layer ( Cd ) should be maintained more than the drug concentration in the organic structure ( Cr ) i.e. , Cd & A ; gt ; Cr ; under such status eq.1 can be written as
dQ/dt = Ps Cd
The skin pervasion dQ/dt becomes a changeless if Cadmium remains changeless throughout the class of skin pervasion. To keep Cd at a changeless value the rate of drug release ( Rd ) should be either changeless or better than rate of skin consumption ( Ra ) i.e. , Rd & A ; gt ; Ra. By this manner the concentration on the surface of tegument ( Cd ) is maintained at equal or greater degree than the equilibrium solubility of drug in stratum horny layer ( Cse ) ; ie Cd & A ; gt ; Cse and a maximal rate of tegument pervasion ( dQ/dt ) m is obtained.
( dQ/dt ) m= PsCse
Apart from the above said ; pervasion besides taken topographic point by diffusion through shunts present in the hair follicles and endocrine secretory organs ( Flynn GL, 1985 ) . 1 cm2 od human tegument outputs 10 hair follicles, 15 greasy secretory organs and 100 perspiration secretory organs. The extremities provide a little fractional surface country of 0.1 % of the entire country.
Recent surveies ( Ilel B, et.al. , 1991 ) shown that the extremities are of import in instance of transdermal soaking up. It is the important path for big polar molecules and ions ( Treager RT, 1996 ) which easy permeates through integral stratum horny layer. The major fraction of most diffusants permeates across the majority of the integral horny bed. The two possible micro tracts serve the stratum horny layer through the transcellular and inter cellular paths.
The tract for the incursion of the drug depends upon the divider coefficient. Most of the diffusants permeate by both the paths ( Elias PM, 1971 ) .
The intercellular tract is the chief path and the major barrier for most of the drug pervasion ( Sanvordeker, et.al. , 1982 and Chein YW, et.al. , 1976 ) .
Polymers FOR TRANSDERMAL DELIVERY
The release of the drug deponds on polymers. Polymers used for the transdermic system should possess following standards.
1. Drug should be soluble and diffusible in the polymer.
2. Polymer should be compatible with excipients.
3. The coveted drug burden and its consequence on polymer unity.
4. It should be compatible with the tegument.
5. It should possess mechanical belongingss like softness, flexibleness, conformability and mechanical unity.
6. Ease of fiction.
7. Polymer should be pure and non toxic.
8. Cost and handiness.
Technology OF TRANSDERMAL DELIVERY SYSTEM
They are classified loosely in to three as shown in the
I. RESERVOIR SYSTEMS
In this type of transdermic system the drug reservoir is packed in between the rate commanding membrane and endorsing bed. The drug release takes topographic point through the microporous or non porous rate commanding membrane. Drug reservoir can be in signifier of solution, suspension or gel or dispersed in a solid polymer matrix. A thin movie of drug compatible, hypoallergenic adhesive polymer can be applied on the outer surface of the polymeric membrane.
Fig.3 a ( Reservoir system )
II. MATRIX SYSTEMS
I ) Drug – in – adhesive system
The drug reservoir is formed by scattering drug in adhesive polymer and so distributing it by solvent projecting method or runing the adhesive on to an imperviable backup bed. A bed of direct polymer is applied over the drug reservoir.
Fig.3 B ( Drug in adhesive system )
two ) Matrix – scattering system
Drug is dispersed in lipotropic or hydrophilic polymer matrix and this polymer phonograph record is fixed over an occlusive base home base. To this a backup bed is attached. An adhesive movie is applied along the perimeter organizing a strip of adhesive rim.
Fig.3 degree Celsius ( Matrix scattering system )
III. MICRORESERVOIR SYSTEMS
It is an combination of reservoir and matrix scattering systems. Here the drugs is foremost suspended in a hydrophilic polymer and so homogeneously to lipophilic polymer. Hence forms several unleachable microscopic domains of drug reservoirs. Thermodynamically unstable reservoir stabilized by cross – associating the polymers.
Fig. 3 vitamin D ( Micro reservoir system )
BASIC COMPONENTS OF TRANSFERMAL DEVICES
Transdermal drug bringing system are designed to back up the transition of drug substances from the surface of tegument, through its assorted beds and into the systemic circulation. There are two basic types of transdermic dosing systems, those that control the rate of drug bringing to the tegument and those that allow the tegument to command the rate of drug soaking up.
The constituents of device induce polymer matrix or matrices that reserve and regulate the release of drug, the drug absorption/permeation, foils and excipients and adhesive to register the readying locally. Figure 4 shows the different constituents of transdermic drug bringing devices.
Fig. 4 Basic constituents of transdermic devices
They helps to ease the soaking up of penetrant through the tegument. They must be pharmacologically inert, non- toxic, non thorn and non – allergic. Must have rapid oncoming of action, can be readily incorporated into the bringing system. Normally used incursion foils are sulfoxides and similar compounds ( Lashmar U, et.al. , 1989 and Sinha VR, et.al. , 2000 ) .
Eg: Dimethyl sulfoxides ( DMSO ) and decyl-methyl sulfoxide ( DCMS ) . Azone, oleic acid, glycerol tricaprylate, lauryl intoxicant, etc. are some other illustrations of incursion foils.